One of the main reasons for loss of sensitivity to hormone
therapy in breast cancer patients is the development of Acquired drug
resistance. Mechanically, the abnormal activation of the Akt / mTOR signaling
pathway and the overexpression of LMTK3, are the main factors involved in the generating
of this résistance.
These factors constitute therefore a very interesting field
of research, and approaches aiming to target this mechanism by abrogating
resistance induced by Akt and lmtk3 are therefore of great relevance of
treatements breast cancer
Lemur tyrosine kinase-3 (LMTK3), a member of the
serine-threonine tyrosine kinase family(1) (2),
plays a central role in endocrine resistance(3)
It has been considered as a promising therapeutic target in the breast cancer
Indeed, this protein is incriminated in the induction of
resistance to hormonal treatment by two mechanisms.
First, it regulates of ESR1 transcriptional activation by
inhibiting PKC, which leads to a decrease of phosphorylated AKT (Ser473), responsible
for the FOXO3 stabilization which allows the increase of the Er? transcriptional
Secondly, it allows the ER? protein direct phosphorylation, protect
it from protease degradation mediated by ubiquitin(Ub)(3).
Thus, in front of resistance to endocrine treatment, inhibition
of LMTK3 resulted in re-sensitization to treatment, and increased AKT
phosphorylation and other unidentified PKC targets(3)
The Akt1 is one of the 3 closely related serine /
threonine-protein kinases (AKT1, AKT2 and AKT3)(5), called AKT kinase. This
protein plays an important role in cell proliferation and survival(6),
It seems to be at the crossroads of different signaling pathways and acts as a
transducer for many functions. (7) (8) (9)
The aberrant expression of LMTK3 and AKT has been observed
in several types of humans cancer, including breast cancer, lung cancer (anaplastic
small cell), bladder cancer(10),
and gastrointestinal cancer(11)
(Gastric and colorectal) (12)
However, recent studies have demonstrated that inhibition of
and pathway (Akt and / or mTOR) deletion , restore sensitivity to anti-estrogen
treatment in breast cancer cells(13),
These are, therefore, two proteins that play a critical role
in the cancer therapy development; (14) (15) (16)
, these molecules have characteristics necessary for design of effective and
reliable small drug molecule.
The identification of lead compounds with a pharmacological
activity against a biological target and the optimization of their properties
are the starting points in the early stages of drug discovery. This discovery
itself is a complex process that would take 12 to 15 years and cost more than $ 1 billion.
The treatment effectiveness is the prerogative of either a
single anticancer molecule with a specific target, or the combination of
several molecules thus aiming different therapeutic targets.
Consequently, the pharmaceutical industry adopted,
firstly, the virtual screening of chemicals products against a relevant therapeutic target as a
means of identifying new lead compounds, and secondly the computational methods
(in silico) in development process of these compounds before the preclinical
stage, particularly in the physicochemical, pharmacodynamic and pharmacokinetic
Quantitative structure-activity relationship (QSAR) models,
are quantitative regression methods which enable to link the chemical structure
to the biological activity. They have extensively been applied in several
chemistry, biology and toxicology(17)
QSAR models are considered a scientifically credible tool for predicting and
classifying biological activities of untested chemicals.
This tool has become an essential method of discovery and
leading edge optimization to direct development (19)
in the pharmaceutical industry.